The Joazeiro lab is interested in understanding how cells know when its macromolecular components are aberrant or damaged, and then decide on ways to either correct or eliminate them. We study this issue in the context of protein quality control (PQC), a process critical for maintaining proteome integrity and cellular fitness; further underscoring its relevance, defective PQC is a hallmark of neurodegenerative diseases. However, despite its importance for both normal cellular function and disease development, only few PQC pathways and mechanisms have been discovered, and, currently, few PQC factors are known to cause neurodegeneration when dysfunctional. This gap in knowledge poses a problem, as it limits progress towards tackling neurodegenerative disease. Among key factors conferring specificity in PQC are E3 ubiquitin ligases. We had previously reported that mutation of the E3 ligase Listerin causes neurodegeneration in mice. In several respects, the Listerin-mutant mice resemble other mouse models of Amyotrophic Lateral Sclerosis (ALS). Consistent with an important biological function, Listerin is conserved in all organisms from yeast to humans. We later discovered that yeast Listerin (Ltn1), functions in a novel process—Ribosome-Associated Protein Quality Control (RQC)—which targets aberrant nascent polypeptide chains for ubiquitination and degradation while they are still attached to ribosomes. These key findings linked, for the first time, RQC and neurodegeneration. Over the past few years, by using yeast as well as biochemical and structural approaches, we and others have made great progress elucidating fundamental aspects of RQC function, although much has yet to be understood. Moreover, to what extent this acquired knowledge is predictive of molecular mechanisms of neurodegeneration remains an open question. To address these issues, two main projects are available:
Ultimately, we expect to provide insights into both cellular strategies of PQC and molecular mechanisms underlying neurodegeneration.
http://www.zmbh.uni-heidelberg.de/Joazeiro/
back to main